FDA Interactions with Drug Advisory Committees A Case Study on Diabetes

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FDA Interactions with Drug Advisory CommitteesA
Case Study on Diabetes

• Paul J. Seligman, M.D., M.P.H.
• Associate Director, Safety Policy Communication
• U.S. Food and Drug Administration
• Royal Danish Embassy Conference
• Copenhagen November 4, 2008

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Objectives

• Provide background on FDA advisory committee
  process
• Discuss the recent Endocrinologic and Metabolic
  Drugs Advisory Committee meeting on the
  cardiovascular assessment of drugs to treat type
  2 diabetes mellitus

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The Value of an Advisory Committee

• Provides independent expert advice
• Lends credibility to the product review process
• Allows for a public discussion of controversial
  issues
• Keeps consumers abreast of trends in product
  development
• Assists in external review of FDAs
• intramural research programs

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Establishment Process

• FDA can request establishment of a new committee
  when
• there is a genuine need for advice
• it is in the public interest to establish such a
  committee
• adequate authority exists for such establishment
  and the authority complies with statutory
  requirements and restrictions

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Advisory Committees are Product and/or Center
Related

• There are

16 in CDER
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Center for Drug Evaluation and Research

• Anesthetic Life Support Drugs
• Anti-Infective Drugs
• Anti-Viral Drugs
• Arthritis Drugs
• Cardiovascular Renal Drugs
• Dermatologic Ophthalmic Drugs
• Drug Safety Risk Management
• Endocrinologic and Metabolic Drugs
• Gastrointestinal Drugs

• Non-Prescription Drugs
• Oncologic Drugs
• Peripheral Central Nervous System Drugs
• Pharmaceutical Science
• Psychopharmacologic Drugs
• Pulmonary-Allergy Drugs
• Reproductive Health Drugs

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Types of Topics Brought Before an Advisory
Committee

• Review of Cutting Edge Scientific Issues
• Product Approval Issues
• Adverse Event Problems
• Labeling Issues
• Guidance Documents

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Who Comprises the Membership?

• Our Stakeholders
• Academicians
• Clinicians
• Consumers
• Industry Representatives
• Patients and/or Patient Care Givers

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FDA Aims for a Diverse Advisory Forum

• FDA wants to have its Advisory Committee members
  mirror the population of America with regard to
• age
• race
• sex
• ethnicity
• geographic location

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Who Can Recommend a Prospective Member?

• Referrals come from
• Former/Current Advisory Committee Members
• FDA Scientists
• Professional Societies and Journals
• Academic Institutions
• Consumer Groups
• Self Nominations
• Congressional Staff
• Industry

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Member Selection(Varies Somewhat by Member Type)

• Public (Federal Register) notice requests
  Nominations
• Résumés reviewed by Product Related area within
  the Agency and recommendation forwarded to the
  Appointing Official
• Screen for Needed Expertise
• Preliminary Screen for Conflicts of Interest
• Consideration is made for Committee Balance
• A letter of invitation is extended by the
  Associate Commissioner for External Relations

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Conflicts of Interest

• Prior to every Meeting each (SGE) member is
  evaluated for any potential conflicts of interest
  relative to the meeting topic

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Conflict of Interest Dilemma

• Experts by definition are engaged in cutting edge
  bench science, clinical trial research and
  independent consulting work.
• By virtue of the above, these individuals are
  sought out by regulated industry to assist in
  product development.

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Who Can Vote?

• NOT EVERYONE
• Statute Dependent
• COI limitations
• Industry Reps
• Consumer Reps
• Patients

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An Important Take Home Message

• Advice from Advisory Committees is thoroughly
  reviewed by the FDA Scientific Staff
• However, decisions and votes are NOT binding on
  the Agency.

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Case Study

• July 1-2, 2008 Endocrinologic and Metabolic Drugs
  Advisory Committee
• Cardiovascular assessment of drugs to treat type
  2 diabetes mellitus
• http//www.fda.gov/ohrms/dockets/ac/08/slides/2008
  -4368s1-00-index.htm

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Introduction

• Anti-diabetic drugs are indicated to improve
  glycemic control and are approved on the basis of
  HbA1c
• Safety concerns with some anti-diabetic drugs
  have led to suggestions for a more extensive
  cardiovascular assessment during the approval
  process

N Engl J Med. 2007357844 N Engl J Med.
20073571775-7
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Introduction

• Advisory committee met to explore this proposal
  and associated complex issues
• Should a long-term cardiovascular trial be
  required?
• Show benefit vs. rule out harm?
• All new therapies or only those with a safety
  signal?
• Challenges related to trial design?
• Timing relative to approval?
• What to do with currently marketed therapies?

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Presentations

• Natural history of type 2 diabetes and
  macrovascular complications (Dr. David Nathan)
• HbA1c as a surrogate for glycemic control and
  microvascular complications (Dr. Robert Ratner)
• Evaluating benefit and risk in type 2 diabetes
  statistical considerations (Dr. Thomas Fleming)
• Clinical macrovascular outcomes with
  anti-diabetic drugs What we already know (Prof.
  Rury Holman)

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Presentations (continued)

• Clinical macrovascular outcomes with
  anti-diabetic drugs Ongoing studies (Dr. Hertzel
  Gerstein)
• Need for cardiovascular assessment during
  approval process for antidiabetic drugs (Dr.
  Steven Nissen)
• Challenges in designing a cardiovascular trial
  for type 2 diabetes (Dr. Robert Califf)

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Type 2 Diabetes Mellitus

• gt150 million people worldwide
• gt18 million people in the United States
• 2-4 fold higher risk of cardiovascular death
• Most deaths due to cardiovascular disease/stroke
• Other important long-term complications
• peripheral vascular disease
• retinopathy, nephropathy, and neuropathy

N Engl J Med. 1998 339229-34 JAMA. 2002
2872570-81 Lancet. 2005 3651333-46
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Points for Consideration/Discussion

• Discuss changes to current design and conduct of
  Phase 2/3 trials that would enhance ability to
  detect CV signal prior to approval and role of
• independent, blinded adjudication committee for
  CV events
• conducting meta-analysis of safety data from all
  Phase 2/3 trials
• adequacy of current safety database required for
  approval ( of patients, duration of exposure)
• Response
• additional assessment should be done compared to
  present procedures
• agreed with use of an independent adjudication
  committee
• majority agreed that meta-analysis of safety data
  may be valuable
• should be standardization of data collected to
  help define safety signals and rule out CV risk

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Points for Consideration/Discussion

• Discuss aspects of design and conduct of
  long-term CV trials
• Should trials objective be to show CV benefit or
  rule out an unacceptable increase in CV risk?
• What should the primary endpoint(s) be (e.g.,
  total mortality, composite endpoints such as
  nonfatal MI, CV death and stroke)?
• What should be the size and duration of any
  long-term CV trials?

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Points for Consideration/Discussion

• Should trials objective be to show CV benefit or
  rule out an unacceptable increase in CV risk?
• conclusive evidence of CV benefit has not been
  demonstrated for any currently available type 2
  drug despite several large, long-term trials
• objective should be to rule out unacceptable risk
• hazard ratio of 1.2-1.4 is reasonable
• difficult to specify magnitude of ratio or
  duration of trial
• depends on type and number of adverse events
  demonstrated in the development program/other
  benefits new drug is offering

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Total Sample Sizes
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Points for Consideration/Discussion

• What should the primary endpoint(s) be (e.g.,
  total mortality, composite endpoints such as
  nonfatal MI, CV death and stroke)?
• recommended using hard endpoints
• Composite clinical endpoints
• Capture both total mortality and individual
  endpoints (e.g., nonfatal MI, stroke)
• What should be the size and duration of any
  long-term CV trials?
• recommended trials with duration between 3-5
  years
• precise determination based on specific
  considerations of a drug

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Questions to the Committee

• It should be assumed that an anti-diabetic
  therapy with a concerning CV safety signal during
  Phase 2/3 development will be required to conduct
  a long-term cardiovascular trial. For those
  drugs or biologics without such a signal, should
  there be a requirement to conduct a long-term
  cardiovascular trial? (vote yes/no requested)
  
• Response
• Yes 14 No 2 Abstain 0

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Questions to the Committee

• If yes, please discuss when such a study should
  be conducted?
• Pre-approval?
• Post-approval? If a long-term cardiovascular
  trial is required post-approval, please discuss
  whether this study should be ongoing at the time
  of approval (i.e., trial already initiated at
  time of approval)
• Response
• Majority suggested starting study during the
  pre-approval period and completing study during
  post-approval period

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Questions to the Committee

• Given that no currently marketed therapy for type
  2 diabetes has established conclusive evidence of
  macrovascular benefit and
• Most marketed therapies for type 2 diabetes have
  not been tested for lack of cardiovascular harm
• Should a requirement for a long-term
  cardiovascular trial be applied to existing
  anti-diabetic therapies?

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Response from Committee

• Believes FDA should not require testing against
  existing agents unless there were specific
  adverse signals
• Discussed techniques to detect possible adverse
  signals in marketed agents

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Next Steps

• Anticipate separate actions for
• sponsors with INDs for drug/biologics under
  development
• type 2 diabetes NDAs currently under review
• drugs already approved
• Complete transcripts of two days available on web
• http//www.fda.gov/ohrms/dockets/ac/08/minutes/200
  8-4368-Final.pdf

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Questions

• Paul J. Seligman, M.D., M.P.H.
• Paul.Seligman_at_fda.hhs.gov
• 301-796-3513